Thoracic positron emission tomographic (PET) scanning after systemic administration of 6-[18F]fluoro-dopamine ([18F]-6F-DA), which we developed to image regional sympathetic innervation and function, is being applied to examine the pathophysiological involvement of myocardial sympathetic nerves in patients with neurologic, cardiac, or psychiatric disorders and to elucidate clinical mechanisms of action of drugs. From time-activity relationships after administration of classical neuropharmacological probes, we obtained evidence that [18F]-6F-DA PET scanning can assess not only cardiac sympathetic innervation but also specific aspects of cardiac sympathoneural function. Patients with peripheral autonomic failure (PAF) had no myocardial [18F]-6F-DA-derived radioactivity, indicating markedly decreased density or absence of myocardial sympathetic nerve terminals. One PAF patient had absent cardiac norepinephrine (NE) spillover and no cardiac PAF [18F]-6F-DA- derived radioactivity, despite normal total body and forearm NE spillover. This suggests that the neurodegenerative process in PAF can include regionally selective loss of sympathetic terminals. Patients with the Shy-Drager syndrome (SDS) had increased cardiac [18F]-6F-DA-derived radioactivity, indicating intact cardiac sympathetic nerve terminals. The rate of decline of the 18F content was slower than normal, suggesting decreased or absent nerve traffic, yet the same patients had normal or increased cardiac norepinephrine spillover. Normal cardiac NE spillover in SDS patients suggested constitutive neurosecretion as the basis for maintenance of approximately normal supine plasma NE levels in these patients. This is the first indication of constitutive neurosecretion in a neurological disease. One patient with advanced SDS had no cardiac [18F]-6F-DA-derived radioactivity, suggesting that the disease can progress to involve peripheral as well as central neurons. In patients with hypertrophic cardiomyopathy (HCM), the overgrown myocardium possesses sympathetic terminals. Several patients had regionally heterogeneous sympathetic innervation, as judged by [18F]-6F-DA-derived radioactivity in the hypertrophic myocardium and mismatches between perfusion, as indicated by 13N-ammonia PET scanning, and sympathoneural images. This might be related to the risk of cardiac arrhythmias in these patients and suggests that interactions between neural and myocardial growth factors contribute to development of the disease. A patient with pain due to reflex sympathetic dystrophy had evidence for decreased sympathetic innervation of the affected limb; the results agreed with those in a rat model of hyperalgesia, where arteriovenous increments in plasma NE levels were smaller on the affected than intact side. The findings therefore indicate that reflex sympathetic dystrophy actually does involve the sympathetic nervous system.